c

RELD OF INVENTION
The present invention relates to a dithioketal compound of formula I and process for its preparation.
BACKGROUND OF INVENTION
US 512448Z and US 5216174 disclose manufacture and use of 4-Fiuoro-a-[2-methy!-l-oxopropyl]y'Oxo-N-[i-diphenylbenzenebutane amide for preparation of [R-(R*,R*)]'2-(4-fluorophenyl)-B,D-dihydroxy -5-(l-methylethyI)-3-phenyI-4-[(phenylamino)carbonyi]-lh-pyrrole-l-heptanoic acid. [R-(R*,R*)]-2-(4-fluorophenyI)-B,D-dihydroxy -5-(l-methylethyl)'3-phenyl-4-[(pheny!amino)carbony!]'lh-pyrrale-l-heptanoic acid is inhibitor of HMG CoA reductase and thus is used as antihypercholesterolemic agent.


SUMMARY OF THE INVENTION
The present invention relates to novel compound of formula I. The present invention also relates to a process for preparation of compound of formula I.

"5


Formula III
where Ri and R2 are any suitable alkyl group or Ri and R2 can join together to form any cyclic structure.
In the other embodiment of the Invention, the compound of formula I can be used to synthesize 4-Fluoro-a-[2-methyl-l-oxopropyl]Y-oxo-N-p-dlphenylbenzenebutaneamide.
DETAILED DESCRIPTION OF THE INVENTION
The compound of formula I is an important intermediate for the preparation of drug molecules especially, HMG Co-A reductase inhibitors. The HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypoiipidemic or hypocholesterolemic agents.


The process of the present invention is also new, economical, and commercially feasible method for preparing intermediate used for the preparation of HMG CoA reductase inhibitors. The process of the present invention is outlined in Scheme I.
The novel process comprises reaction of compound of formula II with compound of formula III.

5"

where Ri and R2 are any suitable alkyl group, preferably C2H5 or Ri and R2 can join together to form any cyclic structures, preferably -CH2"CH2"CH2" .
The reaction between compounds of formula II and III Is carried out in the presence of reagents selerted from n-butyl lithium, NaH or LDA or any such suitable base.
The reaction can also be performed with above mentioned reagents in presence of Copper or Magnesium chloride or any suitable Lewis acid to give compound of formula I in better yield.
■ The compound of formula I can be further used for preparation of 4-Fluoro-a-[2-methyl-l-oxopropyl]Y-oxo-N-p-diphenyl benzene butane amide which is key intermediate for manufacture of [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(l-Methylethyl)-3-Phenyl-4-[(Phenyl amino) Carbonyi]-lh-Pyrrole-l-Heptanoic Acid .
The following non-limiting examples illustrate the inventors' preferred method for preparing the compounds of the invention.
EXAMPLES
Example 1
Preparation of l-[bis(ethylthio)methyn-4-fluorobenzene: A solution of 4-fluoroben2aldehyde (25 g, 0.2 mol) in dry THF (250 ml) was stirred under nitrogen and ethanethiol (21.2 ml, 0.6 mol) and iodine (2.6 g, 0.01 mol) were added. After stirring the reaction mixture for 45 minutes at room temperature, pH of the mixture was adjusted to about 8.0 using 10% aqueous sodium

hydroxide solution. The reaction mixture was extracted with ether (2 x » 100 ml) and combined organic extract was washed with water (2 x 50 ml) brine (2 x 50 ml) and concentrated to obtain title compound. Yield: 20 g, 43.4%. Example 2
Preparation of 2-(4-fluorophenvl)-l,3-dithiane: A solution of 4-fluorobenzaldehyde (20 g, 0.16 mol) in dry THF (200 ml) was stirred under nitrogen and l;3-proanethiol (26 g, 0.24 mo!) and iodine (2 g, 0.008 mol) were added. After stirring the reaction mixture for 2 h, at room temperature, pH of the mixture was adjusted to about 8.0 using 10% aqueous sodium hydroxide solution. The reaction mixture was extracted with ether (2 x 100 ml) and combined organic extract was washed with water (2 x 50 ml) brine (2 x 50 ml) and concentrated to obtain title compound. Yield: 28 g, 79%. Example 3
Preparation of 2-[2,2-bis-ethylsulphanyl-2-(4-fluoro-phenyl)-l-plienyl-ethyl]-4-methyl-3-oxo-pentanoicacid piienylamide: To a chilled solution of l-[bis(ethylthio)methyl]-4-fluorobenzene (5 g, 0.021 mol) in dry THF(50 mi), n-butyi lithium (18 ml, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3-diphenylacrylamide (6.3 g, 0.021 mol) in THF (20 ml) was added to the reaction mixture dropwise, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. After wamiing to room temperature, it was
r7

further stirred for one hour. The reaction mixture was quenched with jvater (50 ml) and extracted with ethyl acetate (2 x 50 ml). Combined organic extract was washed with water (2 x 50 ml) brine (2 x 50 ml) and concentrated to obtain title compound. Yield: 8.5 g, 77%. Example 4
Preparation of 2-[2,2-bis-ethylsulphanyl-2-(4-fluoro-phenyl)-l-phenyl-ethyl]-4-niethyl-3-oxo-pentanoicacid phenylamide: To a chilled mixture of l-[bis(ethylthio)methyl]-4-fluorobenzene (5 g, 0.021 mol) and copper (II) chloride (0.15 g, 0.00011 mol) in dry THF(50 mL), n-butyl lithium (18 mU 0.021 mol) in hexane was added dropwlse under nitrogen atmosphere, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3-diphenylacrylamide (6.3 g, 0.021 mol) in THF (20 mL) was added to the reaction mixture dropwise, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). Combined organic extract was washed with water (2 x 50 mL) brine (2 x 50 mL) and concentrated to obtain title compound. Yield: 9.5 g, 86%. Example 5
Preparation of 2-C[2-(4-fluoro-plienyl)-[l,3]dithian-2-yl]-phenyl-methyl}-4-methyl-3-oxo-pentanoicadd phenylamide: To a chilled solution of 2-(4-fluorophenyl)-l,3-dithiane
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(1 g, 0.005 mol) in dry THF (10 ml), n-butyl lithium (18 ml, 0.021 mol) m hexane was added dropwise under nitnagen atmosphere, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3-dlphenyiacrylamide (1.6 g, 0.0055 mol) in THF (10 ml) was added to the reaction mixture dropwise, maintaining the temperature between -20*^ C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 25 ml). Combined organic extract was washed with water (2 x 25 ml) brine (2 x 25 ml) and concentrated to obtain title compound. Yield: 0.8 g, 54%. Example 6
Preparation of 2-C[2-(4-fIuoro-phenyl)-[l,3]dithian-2-yl]-phenyl-methyl>-4-methyl-3-oxo-pentanoicacid phenylamide: To a chilled mixture of 2-(4-fluorophenyl)-l,3-dithiane (1 g, 0.005 mol) and magnesium chloride (250 mg, 0.00025 mol) in dry THF (10 mL), n-butyl lithium (18 mL, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3-diphenylacrylamide (1.6 g, 0.0055 mol) in THF (10 mL) was added to the reaction mixture dropwise, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 mL) and

extracted with ethyl acetate (2 x 25 mL). Combined organic extract was washed with water (2 x 25 mL) brine (2 x 25 ml) and concentrated to obtain title compound. Yield: 2.0 g, 71%. Example 7
Preparation of 2-[2-(4-fluoro-phenyl-2-oxo-l-phenyl-ethyl3-4-methyl-3-oxo-pentanoic acid phenylamide: To a
stirred solution of red mercury(II) oxide (4.13 g, 0.0190 mol) and boron trifluoride etherate (2.4 ml, 0.019 mol) in 15% aqueous THF (50 ml) a solution of 2-[2,2-bis-ethylsulphanyl-2-(4-fluoro-phenyl)-l-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (5 g, 0.0095 mol) in THF (20 ml) was added dropwise and stirred for 30 minutes. After adding diethyl ether (100 ml), the reaction mixture was filtered. The organic layer was washed with 10% sodium carbonate solution, brine and concentrated. Precipitated product was filtered. Yield; 2 g, 49%. Example 8
Preparation of 2-[2-(4-fluoro-phenyl-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide: A solution of 2-{[2-(4-fluoro-phenyl)-[l,3]dithian-2-yl]-phenyl-methyl}-4-methyl-3-oxo-pentanoic acid phenylamide (5g, 0.0098 mol), copper(II) chloride (2.65 g, 0.02 mol) and copper(II) oxide (3.1 g, 0.04 mol) in 995 aqueous acetone (50 ml) was refluxed for 1 h. The reaction mixture was filtered and concentrated. The residue was redissolved in diethyl ether (50 ml) and filtered again. The filtrate was concentrated and precipitated product was filtered. Yield: 2.2 g, 54%.


n

I
I
KViil^lV'lU" d.ij\pr[y.ni..«il.>VijLil.i\] IJS! (PCT-aj I.IJH.IIOL

, Formula 111 where Ri and Ri are any suitable alkyl group, preferably C2H5
*^ or Ri and R; join together to form any cyclic structures, preferably- CH2-
CHz-CH;-.
3. A process in claim 2, wherein the reaction between compounds of
formula H and HI is carried out in the presence of a base.
4. A process in claim 2, wherein the reaction between compounds of
formula II and III is carried out in the presence of a base and a suitable
Lewis acid.
5. A process in claim 3, wherein the base is selected one or more among n-
butyl lithium, NaH or LDA.
6. A process in claim 4, wherein the Lewis acid is selected from Is salts of copper or magnesium.
7. A compound of formula I as in claim 1, wherein the compound is used for production of 4-Fluoro-a-[2-metbyl-1 -oxopropyl]Y-oxo-M-6-diphenylbenzenebutaneamide.

V.V,i]iiiiVulailO»i.Jirij.niii.JilViili.liiUlJS;iPCT-JJ)iDdiad,i: